Human and animal studies have shown that fetal alcohol exposure increases the incidence of iron deficiency in infancy. Fetal alcohol-related infant iron deficiency is of particular importance in fetal alcohol spectrum disorders (FASD) because it may serve as a mediating mechanism by which alcohol exposure disrupts normal development. Moreover, iron deficiency has been shown to exacerbate the effects of fetal alcohol exposure on growth and neurologic function. In a prospective, longitudinal cohort study, we found that maternal binge drinking was associated with a 70% increase in prevalence of iron deficiency anemia (IDA) at age 6.5 mo. We also found that infants with IDA were markedly more vulnerable to effects of fetal alcohol on growth. Moreover, alcohol exposure and iron status have been shown to affect growth and behavioral outcomes synergistically in a rat model and to affect similar outcomes in humans. The objective of our study is to identify the mechanisms by which fetal alcohol exposure disrupts fetal iron stores and consequently leads to growth and cognitive deficits. Our preliminary data suggest that that the prenatal alcohol-related increase in IDA is due to a reduction in fetal iron stores resulting from disrupted placental iron transfer. We hypothesize that fetal alcohol exposure disrupts placental iron transfer from mother to fetus via two mechanisms: (a) alterations in placental structure that impede transfer of iron to the fetus and (b) altered expression of iron transport proteins, leading to disruption of cellular transplacental iron transport. In the proposed study, we aim to test this hypothesis and to examine the degree to which alcohol-related iron deficiency mediates and/or moderates fetal alcohol effects on somatic growth and neurobehavioral outcomes. We will recruit 90 pregnant women to provide a final sample of 60 mothers-30 heavy drinkers, 30 abstainer/light drinkers-and their infants, we will obtain prospective data on maternal alcohol consumption, diet, and biomarkers of iron status three times during pregnancy, placental samples at delivery, biomarkers of infant iron status at 2 wk and 6.5 mo, and neurobehavioral outcomes at 6.5 mo. First, we will examine the relation of fetal alcohol exposure to (1) placental structural abnormalities that impede nutrient transfer from mother to fetus and (2) alterations in placental iron transport protein expression. Next, we will determine the degree to which alcohol-related placental structural abnormalities and/or disrupted cellular transplacental iron transport mediate effects of fetal alcohol exposure on accretion of fetal iron stores, adjusting for other factors known to affect placental function and iron status, such as maternal iron status, smoking, and other drug use and gestational age at delivery. We will then determine the degree to which diminished fetal iron stores mediate and/or moderate the effects of prenatal alcohol exposure on growth and neurobehavioral function at 6.5 mo postpartum. This study provides an unusual opportunity to test a mechanistic hypothesis regarding the development of FASD directly in human subjects. Identification of mechanisms through which fetal alcohol-related infant iron deficiency mediates developmental sequelae of prenatal alcohol exposure has the potential to transform how we conceptualize the neuropathologic consequences of fetal alcohol exposure. It will also provide foundational knowledge for the NIAAA Strategic Plan for Research goal to use the knowledge gained in uncovering target sites for ethanol's action, such as iron homeostasis, to begin the development of potential therapeutic or preventive interventions for FASD.